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BACKGROUND: With a unique influenza season occurring in the midst of a pandemic, there is interest in assessing the role of the influenza vaccine in COVID-19 susceptibility and severity. METHODS: In this retrospective cohort study, patients receiving a laboratory test for COVID-19 were identified. The primary outcome was comparison of positive COVID-19 testing in those who received the influenza vaccine versus those who did not. Secondary end points in patients testing positive for COVID-19 included mortality, need for hospitalization, length of stay, need for intensive care, and mechanical ventilation. RESULTS: A total of 27,201 patients received laboratory testing for COVID-19. The odds of testing positive for COVID-19 was reduced in patients who received an influenza vaccine compared to those who did not (odds ratio 0.76, 95% CI 0.68-0.86; P

Background: Bicuspid aortic valve (BAV) is associated with an increased risk of aortic dissection, but little is known about pregnancy-associated outcomes. Methods: ICD codes and a text recognition program (EMERSE) were used to identify women with BAV and pregnancy (2000-2018) at a single center. Charts were manually reviewed to confirm the diagnoses, echocardiographic data, co-morbidities, and outcomes. Inclusion criteria were congenital BAV pathology and pregnancy. Primary endpoints included expansion of aortic aneurysm and aortic dissection during pregnancy and up to 6 weeks post-partum. Results: We identified 622 women with diagnoses of BAV and pregnancy. After detailed review, 72 women (87 pregnancies) met inclusion criteria. Mean gestational age at delivery was 36.9 weeks. Ten (11.5%) patients had hypertensive disorders of pregnancy, 7 (8.0%) had gestational diabetes, and 25 (28.7%) were treated with beta-blockers. Two (2.3%) pregnancies had intra-uterine growth restriction. Vaginal deliveries occurred in 56.5% and cesarean section in 36.3%. No Type A or B aortic dissections occurred. During pregnancy, there were no significant changes in the aortic dimensions. Prior to pregnancy, 6 women had aortic measurements > 40mm (mean pre-pregnancy 40.8 ± 3.2 mm; mean post-pregnancy 42.5 ± 3.9 mm). In this higher-risk group, mean gestational age was 38.7 weeks, 4 (66.7%) had vaginal delivery, 1 (16.7%) had preeclampsia, 4 (66.7%) were treated with beta-blockers, and all breastfed. There were no delivery complications, no aortic dissections, and no maternal or fetal deaths. Conclusions: Women with BAV appear to be at relatively low risk for acute aortic dissection during pregnancy.

Importance Thoracic aortic aneurysms leading to acute aortic dissections are a major cause of morbidity and mortality despite significant advances in surgical treatment, which remains the main intervention to prevent type A dissections. In the past 2 decades progress has been made toward a better understanding of molecular mechanisms that lead to aneurysm formation and dissections of the thoracic aorta. This focused review emphasizes the results of clinical trials using β-blocker, losartan potassium, and irbesartan in patients with Marfan syndrome and comments briefly on mechanisms of aortic remodeling, including fibrosis and transforming growth factor β signaling. Observation The major risk factors for the disease are increased hemodynamic forces, typically owing to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease have been shown or are predicted to decrease vascular smooth muscle cell contraction, decrease transforming growth factor β signaling, or alter the extracellular matrix. Preclinical models of Marfan syndrome showed promising results for losartan as a potential therapy to attenuate aortic dilation in mice. However, several clinical trials did not conclusively confirm that losartan attenuated aortic aneurysm expansion better than β-blockers. Most importantly, clinical trials assessing whether losartan therapy not only reduces aortic growth but also improves adverse aortic outcomes, including dissection, need for surgery, and death, have not been conducted. The largest trial to date to our knowledge, the Pediatric Heart Network trial, sponsored by the National Heart, Lung, and Blood Institute, showed a nonsignificant increase in adverse aortic outcomes, with almost a doubling of adverse events in patients randomized to losartan treatment compared with β-blockers, suggesting that this study was underpowered to assess adverse aortic outcomes. On the other hand, the evidence for β-blocker therapy to reduce morbidity and mortality in Marfan syndrome is limited to a single small, prospective randomized and nonblinded clinical trial. Conclusions and Relevance Taken together, these data emphasize the need for clinical trials adequately powered to assess both aortic aneurysm growth and adverse aortic outcomes to identify effective medical therapies for Marfan syndrome and other aortopathies.

Arterial calcification is a feature of atherosclerosis and shares many risk factors including diabetes, dyslipidemia, chronic kidney disease, hypertension, and age. Although there is overlap in risk factors, anti-atherosclerotic therapies, including statins, fail to reduce arterial, and aortic valve calcifications. This suggests that low density lipoprotein (LDL) may not be the main driver for aortic valve disease and arterial calcification. This review focuses on modified LDLs and their role in mediating foam cell formation in smooth muscle cells (SMCs), with special emphasis on enzyme modified non-oxidized LDL (ELDL). In vivo, ELDL represents one of the many forms of modified LDLs present in the atherosclerotic vessel. Phenotypic changes of macrophages and SMCs brought about by the uptake of modified LDLs overlap significantly in an atherosclerotic milieu, making it practically impossible to differentiate between the effects from oxidized LDL, ELDL, and other LDL modification. By studying in vitro-generated modifications of LDL, we were able to demonstrate marked differences in the transcriptome of human coronary artery SMCs (HCASMCs) upon uptake of ELDL, OxLDL, and native LDL, indicating that specific modifications of LDL in atherosclerotic plaques may determine the biology and functional consequences in vasculature. Enzyme-modified non-oxidized LDL (ELDL) induces calcification of SMCs and this is associated with reduced mRNA levels for genes protective for calcification (ENPP1, MGP) and upregulation of osteoblastic genes. A second focus of this review is on the synergy between hyperlipidemia and accelerated calcification In vivo in a mouse models with transgenic expression of human S100A12. We summarize mechanisms of S100A12/RAGE mediated vascular inflammation promoting vascular and valve calcification in vivo.

BACKGROUND: Atrial fibrillation (AF) is associated with death in patients with chronic kidney disease (CKD). We examined the associations between AF and cause-specific mortality in a large CKD population. METHODS: We included 62,459 patients with eGFR 15–59 ml/min/1.73 m(2) (6,639 patients with AF and 55,820 without AF) followed in a large health care system. Outcomes included overall and cause-specific deaths (a) cardiovascular; b) malignancy; and c) non-cardiovascular/non-malignancy causes). Cox regression models for overall mortality and separate competing risk models for each major cause of death category were used to evaluate their respective associations with AF. RESULTS: During a median follow-up of 4.1 years, 19,094 patients died; cause of death was available for 18,854 patients. After multivariable adjustment (demographics, comorbidities, relevant laboratory data, medication use and kidney function), AF was associated with 23% (95% CI: 18%−29%) higher risk of all-cause mortality, 45% (95% CI: 31%−61%) higher risk of cardiovascular mortality and 13% (95% CI: 3%−22%) lower risk of malignancy-related mortality Exclusion of patients with malignancy yielded similar results except for a lack of association between AF and malignancy-related deaths. Results were consistent across various stages of CKD. CONCLUSIONS: In a non-dialysis dependent CKD population, presence of AF was associated with higher all-cause and cardiovascular mortality. These data suggest that patients with both CKD and AF are at high cardiovascular risk, and thus clinical practice (or trials) should aim at reducing the overall excess cardiovascular mortality (not stroke alone) in patients with AF and CKD.

A 55 year-old male with a history of erosive, seropositive rheumatoid arthritis (RA) and interstitial lung disease (ILD) presented with shortness of breath. Echocardiography showed new onset severe left ventricular (LV) dysfunction with an ejection fraction (EF) of 15%, moderately increased mean aortic valve gradient of 20 mmHg in a tri-leaflet aortic valve with severe sclero-calcific degeneration. Coronary angiography revealed no significant obstructive coronary disease. Invasive hemodynamic studies and dobutamine stress echocardiography were consistent with moderate aortic stenosis. Guideline directed medical therapy for heart failure with reduced ejection fraction (HFrEF) was initiated, however diuretics and neurohormonal blockade (beta blocker and angiotensin receptor blocker) provided minimal improvement and the patient remained functionally limited. Of interest, echocardiography performed one year prior to his presentation showed normal LV EF and mild aortic leaflet calcification with moderate stenosis, suggesting a rapid progressing of calcific aortic valve disease. Subsequently, the patient underwent surgical aortic valve replacement (sAVR) and demonstrated excellent post-surgical recovery of LV EF (55%). Calcific aortic valve disease is commonly associated with aging, bicuspid aortic valve, and chronic kidney disease. Pathophysiological mechanism for valvular calcification are incompletely understood, but include osteogenic transformation of valvular interstitial cells mediated by local and systemic inflammatory processes. Several rheumatologic diseases including RA are associated with premature atherosclerosis and arterial calcification, and we speculated a similar role of RA accelerating calcific aortic valve disease. We present a case of accelerated aortic valve calcification with (only) moderate stenosis, complicated by a rapid decline in LV systolic performance. Guidelines for AVR in moderate stenosis without concomitant cardiac surgery are not well established, though it should be considered in selected patients.

© 2014 American Heart Association, Inc. Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.

Objective— S100A12 and fibroblast growth factor 23 are biomarkers of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. Approach and Results— A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9, and S100A12 was expressed in C57BL/6J mouse (hBAC-S100) to generate a novel humanized mouse model. CKD was induced by ureteral ligation, and hBAC-S100 mice and wild-type mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased fibroblast growth factor 23 in the hearts, left ventricular hypertrophy, diastolic dysfunction, focal cartilaginous metaplasia, and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in wild-type mice with CKD or in hBAC-S100 mice lacking the receptor for advanced glycation end products with CKD, suggesting that the inflammatory milieu mediated by S100/receptor for advanced glycation end products promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including interleukin-6, tumor necrosis factor-α, lipopolysaccarides, or serum from hBAC-S100 mice upregulated fibroblast growth factor 23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Conclusions— Myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a receptor for advanced glycation end products–dependent manner in a mouse model of CKD. We speculate that fibroblast growth factor 23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate left ventricular hypertrophy and diastolic dysfunction in hBAC-S100 mice with CKD.

The measurement of cardiac troponins (cTn) is widely used to diagnose myocardial injury or necrosis 1, 2 , and has become an important tool for the risk stratification and clinical management of patients with acute coronary syndrome (ACS) 3, 4 . However, elevated cTn levels are also found in non-ACS patients 5 . For example, in a recent study of patients with chronic stable coronary artery disease, higher cTn levels were observed in patients with concomitant kidney disease or diabetes mellitus 6, 7 . Furthermore, approximately 15% of patients with acute ischemic stroke have elevated cTn 8-11 ; many of whom, have no other clinical manifestation of acute coronary ischemia. Because cTn still provides important prognostic information regarding mortality outcomes in stroke patients 12 , current AHA guidelines recommend its measurement in all patients presenting with acute ischemic stroke 13 . However, the role of cTn in predicting culprit or obstructive coronary lesions in these patients remains unknown, but may be important to ascertain if subsequent revascularization therapy could be shown to be beneficial.

Elevated cardiac troponin (cTn) signals myocardial necrosis and injury but does not specify the mechanism of that injury. The measurement of cardiac troponins is widely used to diagnose myocardial infarction and has become an important tool for the risk stratification and clinical management of patients with acute coronary syndrome

ObjectivesThe objective of this study was to examine the similarities and differences in Caucasian (C) and African-American (AA) patients with bicuspid aortic valve (BAV) with respect to morphology, severity of aortic stenosis/insufficiency, and aortic dilation.BackgroundBAV is a common congenital valve abnormality, accounting for a large number of valve replacements.MethodsA total of 229 patients with the diagnostic code BAV were identified retrospectively from our computerized adult echocardiographic database, which consists of 91,896 studies performed at the University of Chicago Medical Center from 1998 to 2009, representing 40,878 patients. Of those, 183 patients with BAV were included in this retrospective BAV single-center cohort study and reanalyzed with a comprehensive assessment of aortic dimensions, aortic valve morphology and function, clinical cardiovascular risk factors, and patient characteristics.ResultsOf the 183 patients with BAV, 138 were C and 45 were AA. Our echocardiographic database encompasses approximately 65% AA, 31% C, and 4% other races, for an estimated frequency of BAV in AA patients of 0.17% and a frequency in C patients of 1.1% (p = 0.001). There were no significant inter-racial differences regarding sex, height, weight, hyperlipidemia, diabetes, tobacco use, cardiac medications, and left ventricular ejection fraction. The AA cohort was older (age 50 ± 17 years vs. 43 ± 17 years, p < 0.05) and had a higher prevalence of hypertension (51% vs. 24%, p < 0.05). After adjusting for comorbidities, aortic dimensions were larger in C (C vs. AA: annulus, 2.4 ± 0.4 vs. 2.1 ± 0.4 cm; sinuses of Valsalva, 3.4 ± 0.7 vs. 3.1 ± 0.6 cm; sinotubular junction, 3.0 ± 0.6 vs. 2.6 ± 0.5 cm; and ascending aorta, 3.5 ± 0.7 vs. 3.2 ± 0.5 cm; all p values

We report a case of congenital bicuspid aortic valve infective endocarditis in an 18-year-old male with no significant past medical history. He presented to the emergency department from an ophthalmology clinic with new right-eye vision changes. Initial EKG revealed sinus tachycardia and he was hemodynamically stable. Expedited diagnostic transesophageal echocardiography revealed vegetations on both aortic leaflets, an aortic root abscess, and a fistulous tract extending from the left ventricular outflow tract into the right ventricular outflow tract. Although he was evaluated by the cardiothoracic surgery team and scheduled for operative repair, he acutely became bradycardic, developed pulseless electrical activity, and was resuscitated on multiple occasions, but died suddenly from PEA arrest within 24 hours of presenting to the emergency department. This case demonstrates complications of acute bacterial endocarditis. We discuss the current debate surrounding the role of antibiotic prophylaxis for infective endocarditis. Additionally, we suggest that patients with a bicuspid aortic valve, a common congenital defect with a known increased risk for bacterial endocarditis, might represent a unique cohort to prospectively study whether antibiotic prophylaxis reduces the incidence, morbidity, and mortality of bacterial endocarditis in patients at increased risk.

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.

Background: Cardiovascular disease including left ventricular hypertrophy, diastolic dysfunction and ectopic valvular calcification are common in patients with chronic kidney disease (CKD). Both S100A12 and fibroblast growth factor 23 (FGF23) have been identified as biomarkers of cardiovascular morbidity and mortality in patients with CKD. We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. Methods: This review paper focuses on S100 proteins and their receptor for advanced glycation end products (RAGE) and summarizes recent findings obtained in novel developed transgenic hBAC-S100 mice that express S100A12 and S100A8/9 proteins. A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9 and S100A12 was expressed in C57BL/6J mice (hBAC-S100). CKD was induced by ureteral ligation, and hBAC-S100 mice and WT mice were studied after 10 weeks of chronic uremia. Results: hBAC-S100 mice with CKD showed increased FGF23 in the heart, left ventricular hypertrophy (LVH), diastolic dysfunction, focal cartilaginous metaplasia and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in WT mice with CKD or in hBAC-S100 mice lacking RAGE with CKD, suggesting that the inflammatory milieu mediated by S100/RAGE promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including IL-6, TNF, LPS, or serum from hBAC-S100 mice up regulated FGF23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Conclusions: Taken together, our study shows that myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a RAGE dependent manner in a mouse model of CKD. We speculate that FGF23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate LVH and diastolic dysfunction in hBAC-S100 mice with CKD. We suggest that S100/RAGE-mediated chronic sustained systemic inflammation is linked to pathological cardiac remodeling via direct up regulation of FGF23 in cardiac fibroblasts, thereby providing a new mechanistic understanding for the common association between CKD, diabetes, metabolic syndrome, or hypertension with left ventricular hypertrophy with diastolic dysfunction.

IL22 belongs to the IL10 cytokine family and is expressed by T helper cells. IL22 functions on epithelial cells and has been shown to improve epithelial barrier function in inflammatory bowel disease, asthma, and psoriasis; autoimmune diseases associated with elevated serum IL22. Patients with psoriasis have increased coronary artery disease and it was previously shown that macrophages from patients with psoriasis have impaired cholesterol efflux. The function of IL-22 on macrophage cholesterol metabolism is not known. Methods: ABCA1, ABCG1 and CD36 mRNA and protein expression, cholesterol uptake and efflux were studied in murine macrophages and human THP-1 macrophages. C57BL6/J mice with transgenic expression of hS100A12 and hS100A8/9 in myeloid cells were generated by using a bacterial artificial chromosome (hBAC/S100 mice). hBAC/S100 and WT littermate mice were breed into mice lacking the receptor for advanced glycation endproducts, RAGE. Results: Peritoneal macrophages from hBAC/S100 mice have reduced ABCG1 mRNA and protein expression, increased cholesterol uptake, and reduced cholesterol efflux compared to WT. This was abolished in hBAC/S100 mice lacking RAGE, the receptor for S100/calgranulin. Recombinant S100A12 or S100A8 protein (2.5 μg/ml) had no effect on ABCG1 expression in WT peritoneal macrophages or human THP-1 cells, suggesting other systemic intermediary products in hBAC/S100 mice. Serum IL22 and mRNA in splenic T cells were significantly increased in hBAC/S100 mice, and this was abolished in hBAC/S100 mice lacking RAGE. Moreover, r S100A12 increased IL22 mRNA by 2-fold in cultured human THP-1. Importantly, THP-1 macrophages treated with r IL22 (100 ng/ml) had reduced expression of ABCG1 and impaired cholesterol efflux to mouse serum, but not to Apoa1. Up regulation of ABCG1 and ABCA1 in response to LXR agonist TO901317 in THP-1 cells abolished the detrimental effects of IL22 on cholesterol efflux. Conclusion: S100/calgranulin induces IL22 in a RAGE dependent manner. IL22 down regulates ABCG1 and impairs cholesterol efflux in macrophages. This raises the hypothesis that IL22-mediated down regulation of cellular cholesterol efflux may be linked to improved epithelial barrier function, but may also augment atherosclerosis.

Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta, coronary, carotid and peripheral arteries becomes more prevalent with age. Genomewide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss of function mutations in ENPP1 an enzyme that produces extracellular pyrophosphate. Adult onset vascular calcification is linked to mutations NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle itself as well as the matrix. Herein we will review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification.

Advanced glycation end products (AGEs) are chemically heterogeneous structures and include such specific forms as carboxy (methyl)lysine, pentosidine and others, and were previously measured in heart failure patients as serum AGE, skin AGE, and AGE in cardiomyocytes and vascular cells within the heart. The study by Nozynski et al.1 adds to this body of knowledge as it examines AGE expression directly in explanted hearts: 22 with cardiomyopathy (CMP) and diabetes (DM), 114 with CMP without DM, 20 healthy heart donors, and 14 with DM without CMP. One of the main findings in this study was equally increased AGE accumulation in intramyocardial veins, arterioles and venules in diabetic subjects with and without CMP. This is an unexpected finding, since it is believed that AGE may contribute to mechanical (stiffness) as well as molecular (inflammation) changes contributing to myocardial dysfunction. However, we would like to offer a hypothesis for this unexpected result not raised by the authors. The diabetic cohort without CMP consists of patients who died in the first 24 hours after admission to the intensive care unit due to cerebral injury, and therefore represent a very sick cohort. It is well established that trauma is associated with a high burden of systemic inflammation, oxidative stress and for instance serum myeloperoxidase activity is highest in the first 6 hours in non-surviving patients with head trauma2. Moreover, inflammation, reactive oxygen species and myeloperoxidase enzymatic activity promotes protein glycation and AGE formation as rapidly as in 60 minutes3. AGE formation in human tissue is a dynamic process as recently demonstrated by the rapid decline of AGEs in myeloperoxidase-positive inflammatory cells in carotid endarterectomy tissue after treatment with simvastatin prior to surgery4. We speculate that the increased accumulation of AGE in the heart of diabetic subjects without CMP found in the study by Nozynski et al. may be largely explained by the circumstances of this study. The authors cannot exclude the possibility of rapid AGEs formation as a result of enhanced oxidative stress and myeloperoxidase activity associated with lethal trauma in this diabetic control group without CMP. Further studies examining AGE in cardiac tissue are needed to dissect the role of AGE in heart failure. Most importantly, more in-depth analysis of the specific AGEs and their concentrations in these tissues must be performed. Indeed, the concept of the heterogeneous nature of AGEs is underscored in Nyzynski’s study population and design.

Background: The proinflammatory cytokine S100A12 (also known as EN-RAGE) is associated with cardiovascular morbidity and mortality in hemodialysis patients. In the cur- rent study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in nonatherosclerosis-prone C57BL/6J mice on normal rodent chow diet, but exposed to the metabolic changes of chronic kidney disease (CKD), would develop vascular disease resembling that observed in patients with CKD. Methods: CKD was induced in S100A12 transgenic mice and wild-type littermate mice not expressing human S100A12 by surgical ligation of the ureters. The aorta was analyzed after 7 weeks of elevated BUN (blood urea nitrogen), and cultured aortic smooth muscle cells were studied. Results: We found enhanced vascular medial calcification in S100A12tg mice subjected to CKD. Vascular calcification was mediated, at least in part, by activation of the receptor for S100A12, RAGE (receptor for advanced glycation endproducts), and by enhanced oxidative stress, since inhibition of NADPH-oxidase Nox1 and limited access of S100A12 to RAGE attenuated the calcification and gene expression of osteoblastic genes in cultured vascular smooth muscle cells. Conclusion: S100A12 augments CKD-triggered osteogenesis in murine vasculature, reminiscent of features associated with enhanced vascular calcification in patients with chronic and end-stage kidney disease.

Objective— The proinflammatory cytokine S100A12 is associated with coronary atherosclerotic plaque rupture. We previously generated transgenic mice with vascular smooth muscle–targeted expression of human S100A12 and found that these mice developed aortic aneurysmal dilation of the thoracic aorta. In the current study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in atherosclerosis-prone apolipoprotein E (ApoE)–null mice would accelerate atherosclerosis. Methods and Results— ApoE-null mice with or without the S100A12 transgene were analyzed. We found a 1.4-fold increase in atherosclerotic plaque size and more specifically a large increase in calcified plaque area (45% versus 7% of innominate artery plaques and 18% versus 10% of aortic root plaques) in S100A12/ApoE-null mice compared with wild-type/ApoE-null littermates. Expression of bone morphogenic protein and other osteoblastic genes was increased in aorta and cultured vascular smooth muscle, and importantly, these changes in gene expression preceded the development of vascular calcification in S100A12/ApoE-null mice. Accelerated atherosclerosis and vascular calcification were mediated, at least in part, by oxidative stress because inhibition of NADPH oxidase attenuated S100A12-mediated osteogenesis in cultured vascular smooth muscle cells. S100A12 transgenic mice in the wild-type background (ApoE+/+) showed minimal vascular calcification, suggesting that S100A12 requires a proinflammatory/proatherosclerotic environment to induce osteoblastic differentiation and vascular calcification. Conclusion— Vascular smooth muscle S100A12 accelerates atherosclerosis and augments atherosclerosis-triggered osteogenesis, reminiscent of features associated with plaque instability.